PHYSICAL ASSOCIATION AND FUNCTIONAL ANTAGONISM BETWEEN THE P65 SUBUNIT OF TRANSCRIPTION FACTOR NF-KAPPA-B AND THE GLUCOCORTICOID RECEPTOR
PHYSICAL ASSOCIATION AND FUNCTIONAL ANTAGONISM BETWEEN THE P65 SUBUNIT OF TRANSCRIPTION FACTOR NF-KAPPA-B AND THE GLUCOCORTICOID RECEPTOR
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DOI：
10.1073/pnas.91.2.752
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发表时间：
1994-01-18
影响因子：
11.1
通讯作者：
PREFONTAINE, KE
中科院分区：
文献类型：
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作者：
RAY, A;PREFONTAINE, KE
糖皮质激素被广泛用作抗炎药，下调白细胞介素6基因和其他参与炎症反应的细胞因子基因的表达。相反，转录因子NF-kappa B是Rel转录因子家族的一员，与诱导参与免疫和炎症反应早期过程的多个基因有关。这促使我们研究糖皮质激素发挥其抗炎活性的机制之一是否通过抑制NF-kappa B介导的基因激活。我们报道，在完整细胞中，NF-IL6因子和NF-kappa B的p65亚基组合激活的白细胞介素6启动子被地塞米松（配体）激活的糖皮质激素受体抑制。相反，p65的过表达抑制了地塞米松和糖皮质激素受体联合激活小鼠乳腺肿瘤病毒启动子。此外，我们在蛋白质交联和共免疫沉淀实验中提供了糖皮质激素受体和p65之间物理关联的证据，使用体外翻译蛋白或存在于细胞提取物中的蛋白。这些研究表明，NF-kappa B与糖皮质激素受体之间的直接相互作用可能部分解释了糖皮质激素在体内的抗炎特性。
Glucocorticoids, which are widely used as antiinflammatory agents, downregulate the expression of the interleukin 6 gene and of additional cytokine genes involved in inflammatory responses. Conversely, the transcription factor NF-kappa B, a member of the Rel family of transcription factors, has been implicated in the induction of multiple genes involved in the early processes of immune and inflammatory responses. This prompted us to investigate whether one of the mechanisms by which glucocorticoids exert their antiinflammatory activities is through inhibition of gene activation mediated by NF-kappa B. We report that, in intact cells, activation of the interleukin 6 promoter by a combination of the factor NF-IL6 and the p65 subunit of NF-kappa B is inhibited by dexamethasone (ligand)-activated glucocorticoid receptor. Conversely, activation of the mouse mammary tumor virus promoter by a combination of dexamethasone and glucocorticoid receptor is inhibited by overexpression of p65. Furthermore, we provide evidence for physical association between glucocorticoid receptor and p65 in protein crosslinking and coimmunoprecipitation experiments, using either in vitro translated proteins or those present in cell extracts. These studies suggest that direct interactions between NF-kappa B and glucocorticoid receptor may partly account for the antiinflammatory properties of glucocorticoids in vivo.